There is a set of molecules known as chiral molecules which have identical chemical formulas, but have a different spatial distribution. These molecules have very similar physical and chemical properties, which makes it difficult to separate them using conventional methods used in the chemical industry (crystallization, adsorption, etc.). On the other hand, unlike the physical and chemical properties, the biological properties of these molecules can be extremely different, e.g., a molecule with a three-dimensional arrangement can affect a living organism, while another one with the inverse arrangement can act as medication. This type of phenomena is common and widely known in the chemistry of enzymes. The chemistry of nature is stereoselective, i.e., it favors the formation of only one of the two three-dimensional arrangements that the chiral molecules can have. Each compound with a determined three-dimensional arrangement is called an “enantiomer”.
A large quantity of medications available in the market use chiral molecules as active ingredients. Since 1992, the FDA prohibited the use of racemic mixtures (50/50 mixture of enantiomers) when one of the enantiomers has an unknown or adverse pharmacological activity. Currently, the pharmaceutical industry directs its efforts to offering enantiomerically pure medications. However, to date, there are still medications sold as racemic mixtures. When it is confirmed that any of the enantiomers has adverse effects to the organism it is obligatory to separate the mixture of enantiomers until only the desired active enantiomer is obtained.
As previously mentioned, enantiomers have very similar physical and chemical properties which makes it difficult to separate them. The preferred procedure for the production of pharmaceuticals involves the synthesis of racemic mixtures using non-selective catalysts, and once the racemic mixture is obtained, a series of separations is done by means of diastereomeric resolution until the desired purity of the active enantiomer is achieved. In order to achieve the separation, an enantiomerically pure compound (generally obtained from a natural source) is used, which is made to react with the racemic compound so as to obtain a mixture of diastereomers. Unlike enantiomers, diastereomers have different physical properties, which allows their separation (generally through crystallization). Once separated, the inverse reaction for forming the diastereomers is carried out in order to obtain the desired enantiomer and recover the auxiliary chiral compound used in the separation, which can be recycled. This process generates low yields and useless byproducts.
An alternative process has been proposed which postulates using a stereoselective catalyst during the synthesis of the chiral compound; this favors the formation of one enantiomer, reducing or preventing the need for purification processes after the reaction.
Since approximately a decade ago, stereoselective compounds have been actively sought out. The chiral catalysts most investigated involve “organometallic” molecules which include in their formation precious metals such as Pt, Pd, Rh, etc. Generally, these types of catalysts are sensitive to oxidizing atmospheres, which causes greater difficulty in handling during their synthesis and in their use to catalyze the production of chiral molecules. Moreover, these catalysts are homogeneous, so it is necessary to carry out a separation of the catalyst and the reaction mixture, downstream. In order to avoid this final difficulty, it has been proposed to bind organometallic catalysts to various substrates (U.S. Pat. No. 6,028,025 and U.S. Pat. No. 5,990,318).
As an alternative to the organometallic catalysts, there are the so-called “organocatalysts.” These are organic chiral molecules that do not contain metals within their formation (U.S. Pat. No. 8,084,641, U.S. Pat. No. 7,541,456, and U.S. Pat. No. 7,291,739). One of its main advantages is that they are not sensitive to oxidizing atmospheres, however, because they are less active than organometallic catalysts, they require greater reaction times. These catalysts are also homogeneous. However, to date, few efforts have been made to immobilize these type of systems in solid matrices (U.S. Pat. No. 8,148,287; K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem. Soc. 123, 5260-5267, 2001; F. Calderón, R. Fernández, F. Sánchez, A. Fernández-Mayoralas, Adv. Synth. Catal. 347, 1395-1403, 2005; and E. G. Doyagüez, F. Calderón, F. Sánchez, A. Fernández-Mayoralas, J. Org. Chem. 72, 9353-9356, 2007). In U.S. Pat. No. 8,148,287, the anchor of organic catalysts is reported in a silicone foam using 1,2,3-triazole as linker between the inorganic and the organic part. F. Calderón et al. and E. G. Doyagüez et al. are developing a method for the synthesis of heterogeneous chiral catalysts using 4-hydroxyproline as organic catalyst, which is anchored to previously synthesized oxide supports MCM-41, silica, ITQ2 and ITQ6. The amino acid is anchored to the solid matrix through the hydroxyl group.
In a similar manner, K. Sakthivel et al. uses a method of proline immobilization in a silica gel support. However, the amino acid is not covalently bonded to the support. There is a recent report in which proline anchored to mesostructured catalysts (MCM-41) was synthesized in just one step; however, this synthesis process involves the use of colloidal silica previously synthesized as a substrate for the anchoring (E. A. Prasetyanto, S. C. Lee, S. M. Jeong, S. E. Park, Chem. Commun. 1995-1997, 2008). In this procedure, the amino acid is anchored to the MCM-41 in the carboxyl group of the proline. In general, the processes used to immobilize the organic catalysts involve the anchoring of the organic catalyst by means of the formation of covalent bonds with a previously synthesized oxide surface, which allows the maximum anchoring of approximately 10% in weight of the organic catalyst.
Very recently, Garcí a-Doyagüez et al. in 2009, described in Spanish Patent No. 2349604 the construction of an organic polymer of hydroxyproline and its use as catalyst. The invention uses organic polymers based on vinyl monomers, and reports activity in aldol condensation with minimum reaction times of 24 hours and 97% conversion, obtaining enantiomeric selectivity with 1:1 proportion for the most active catalyst.
The reported reaction times to achieve conversions greater than 80% during aldol condensation reactions vary from 24 to 72 hours when homogeneous organic catalysts are used (K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem. Soc. 123, 5260-5267, 2001), of approximately 24 to 48 hours for heterogeneous catalysts, obtained by traditional anchoring methods available in the literature (F. Calderón, R. Fernández, F. Sánchez, A. Fernández-Mayoralas, Adv. Synth. Catal. 347, 1395-1403, 2005; E. G. Doyagüez, F. Calderón, F. Sánchez, A. Fernández-Mayoralas, J. Org. Chem. 72, 9353-9356, 2007), while the visible reaction time when using the catalysts obtained through the methodology described in this invention varies from 2 to 6 hours.
This invention reports a new and innovative methodology in the synthesis of heterogeneous chiral catalysts, and generates the silicone oxide solid matrix using functionalized monomer with the organic catalyst properly protected, which allows obtaining solid heterogeneous chiral catalysts with approximately 30% in weight of the organic catalyst. The synthesis process includes four stages of reaction that are low cost and simple to develop, with high yield, and that do not use sophisticated purification processes. Only in stages 3 and 4 is the solid product purified by simple washing with organic or aqueous solvent. Furthermore, the catalysts obtained in this invention catalyze condensation reactions in a stereoselective manner.